Controlled release system and nanoparticulate polymeric carriers such as micelles, are considered to be promising candidates for the targeted delivery of drugs. Such polymeric devices for the targeted delivery can contain a broad variety of bioactive ingredients, among which hydrophobic drugs. Reference is made to WO2010/033022 wherein a method for the preparation of a controlled control release system is disclosed. It discloses a method for entrapment of compounds in polymer carriers for controlled release of active ingredients, preferably bioactive ingredients, such as drugs. This method results in a system for controlled release of active ingredients and especially for controlled drug delivery.
In accordance with the present invention, the term “controlled release” encompasses all kinds of controlled release, including slow release, sustained and delayed release. Particularly, the present invention results in active ingredients, entrapped in or otherwise incorporated in or coupled to polymer carriers or polymeric devices, such as micelles, nanoparticles, microspheres, hydrogels and other types of polymer carriers or devices for controlled release; the active ingredients are bonded to, and especially covalently bonded to these polymeric devices or carriers.
Nanoparticulate carriers and controlled release systems are often administered intravenously, however it would be desirable to have other administration routes available. Other administration routes, such as subcutaneous administration, intralympatic administration, of liposomes and micelles have been used, but with mixed results. See for example Dhanikula et al. Curr Drug Deliv. 2005 January; 2(1):35-44, Sakakura, et al. Anti-Cancer Drugs 3 (1992), pp. 233-236, Reddy et al., J. Control Release 105 (2005) 185-198, Cai et al., J Surg Res 147, (2008) 247-252, Maincent, Pharmac Res 9 (1992) vol 12, Nishioka and Yoshino, Adv Drug Deliv Rev 47 (2001) 55-64.
Upon subcutaneous administration, nanocarriers do not have direct access to bloodstream. They either enter lymphatic capillaries draining the injection site or remain at the site of injection. Once nanoparticles traverse through interstitium to enter lymphatic capillaries, they pass through the lymphatic system where they either are captured by lymph node, or continue to reach bloodstream. For those particles remaining at the injection site, destabilization and degradation take place with time, thereby possibly releasing the therapeutic agents. This release of the therapeutic agent at the injection site, including premature or burst release as a result of an instable particle may have toxic effect and may harm the injection site, causing inflammation and discomfort to the patient. The resulting small molecules (MW<16 k Dalton) can pass through the pores in the blood capillary walls while large particles are being transported by lymphatics. The passage of small molecules, e.g. therapeutic agent, directly into the blood stream is often not desirable. The encapsulation of an agent in a nanoparticle was often intended to provide a slow or sustained release of the therapeutic agent. When the therapeutic agent is released directly into the blood stream such a sustained release is not possible anymore. When the nanoparticle is also targeted to go to a specific site, when the nanoparticle is degraded in the injection site and only the therapeutic agent is released in the blood, the targeting action is also no longer present.
According to Oussoren and Storm (Adv Drug Del Rev 50 (2001) 143-156) size is a decisive factor influencing lymphatic absorption and lymph node uptake of subcutaneous administration. Generally, other factors such as lipid composition, charge and the presence of a hydrophilic PEG-coating on the liposome surface may have an affect lymphatic absorption and lymph node uptake of s.c. administered liposomes, however the results as shown in the prior art are very mixed, and often contradict each other. It was found that about 1-2% of the injected dose is taken up by regional lymph nodes. For small (0.1 μm), neutral liposomes, the degree of lymphatic absorption can reach levels up to 70% of the injected dose. However, it should be taken into account that even after injection of liposome dispersions with a small mean size a substantial fraction of the injected dose remains at the injection site. It was also shown that the anatomical site of injection had a large influence on uptake after s.c. injection (Oussoren 2001, Adv. Drug Del Rev 50 p 143-156). After injection into the flank, liposomes remained mostly at the site of injection (about 95%), whereas injection into the foot, about 40% of the injected dose was taken up from the injection site. Also the uptake into lymph nodes was significantly lower for injection at the flank (less than 0.1%) than for injection at the dorsal side of foot or footpad (about 0.5-0.8%). It is thought that pressure in interstitial tissue is an important factor determining the uptake of liposomes from the injection site. In rats, there a less interstitial space in the foot than in the loose tissue of the flank. Injection into the foot may induce a rise in local interstitial pressure in the foot due to the limited space and thereby contribute to the increased uptake of the injected liposomes. Unfortunately the foot is not a first choice of injection site for s.c. injections.
There is thus a need for control release system such as nanoparticles and micelles that may administered other then intravenously. Preferably these particles are easily taken up by the lymphatic system and then are taken up by the lymph node and/or are passed through to the bloodstream. Preferably, the nanoparticles stay stable at the administration site and do not degrade so to release the therapeutic or active agent. It is also desirable to have a control release particle that may carry different active agents without having an effect on the uptake and/or stability of the control release particle. Preferably the control release particle may comprise linkers, such as degradable linkers, so that the covalently entrapped active agent may be released on a desired location or time. Preferably the control release particle may accommodate different linkers without an effect on the uptake and/or stability of the control release particle.
The control release systems of WO2010/033022 have all been given by intravenous administration. These particles show long circulation times in the blood circulation and because the drugs are covalently bound to the particles via biodegradable bonds they show sustained plasma levels including therapeutic levels
Surprisingly it has been found that the control release system of WO2010/033022 also has good properties when administered in routes other than intravenously.